Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic diseases, and these terms are considered synonymous. Genetics (from the Greek genno γεννώ= give birth) is the science of genes, heredity, and the variation of organisms. ... A disease is any abnormal condition of the body or mind that causes discomfort, dysfunction, or distress to the person affected or those in contact with the person. ... Santorio Santorio (1561-1636) in his steelyard balance, from Ars de statica medecina, first published 1614 Metabolism (from μεταβολισμος(metavallo), the Greek word for change), in the most general sense, is the ingestion and breakdown of complex compounds, coupled with the liberation of energy, and the consequent generation of waste... This stylistic schematic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). ... Neuraminidase ribbon diagram An enzyme (in Greek en = in and zyme = leaven) is a protein, or protein complex, that catalyzes a chemical reaction and also controls the 3D orientation of the catalyzed substrates. ... The word substrate can mean the following: In biochemistry, a substrate is a molecule which is acted upon by an enzyme. ...

The term inborn error of metabolism was coined by a British physician, Archibald Garrod (1857-1936), in the early 20th century. He is known for the "one gene, one enzyme" hypothesis, which arose from his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism (http://www.esp.org/books/garrod/inborn-errors/facsimile/|) was published in 1923. Sir Archibald Edward Garrod was an English physician who pioneered the field of inborn errors of metabolism. ... Alkaptonuria also known as alcaptonuria or ochronosis is a rare inherited genetic disorder of tyrosine metabolism. ...

Major categories of inherited metabolic diseases

Traditionally the inherited metabolic diseases were categorized as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class. Many others do not fall into these categories. Carbohydrates (literally hydrates of carbon) are chemical compounds that act as the primary biological means of storing or consuming energy, other forms being fat and protein. ... In chemistry, an amino acid is any molecule that contains both amino and carboxylic acid functional groups. ... An organic acid is an organic compound that is an acid. ... The lysosomal storage diseases are a group of over thirty disorders that result from defects in lysosomal function. ...

• Disorders of carbohydrate metabolism
  • E.g., glycogen storage disease
• Disorders of amino acid metabolism
  • E.g., phenylketonuria
• Disorders of organic acid metabolism
  • E.g., maple syrup urine disease
• Disorders of fatty acid oxidation and mitochondrial metabolism
  • E.g., medium change acyl CoA dehydrogenase deficiency
• Disorders of porphyrin metabolism
  • E.g., acute intermittent porphyria
• Disorders of purine or pyrimidine metabolism
  • E.g., Lesch-Nyhan syndrome
• Disorders of steroid metabolism
  • E.g., congenital adrenal hyperplasia
• Disorders of mitochondrial function
  • E.g., Kearns-Sayre syndrome
• Disorders of peroxisomal function
  • E.g., Zellweger syndrome
• Lysosomal storage disorders
  • E.g., Gaucher's disease

Glycogen storage disease is any one of several inborn errors of metabolism that result from enzyme defects that affect the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types. ... Phenylketonuria fee-nil-kee-ton-yur-ee-aah+ (PKU) is a human genetic disorder that occurs in about 1 in 15,000 births, but the incidence varies widely in different human populations from 1 in 4,500 births among the Irish to fewer than one in 100,000 births among... Maple syrup urine disease (MSUD) is an inherited genetic disorder in which the body is unable to process certain amino acids properly, unmetabolised amino acids are passed in the urine giving it a distinctive maple syrup odour. ... The porphyrias are inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway (also called porphyrin pathway). ... Lesch-Nyhan syndrome, or LNS, is a serious genetic disorder that affects mostly males. ... Congenital adrenal hyperplasia (CAH) refers to any of several autosomal recessive diseases resulting from defects in steps of the synthesis of cortisol from cholesterol by the adrenal glands. ... Zellweger syndrome is a rare, congenital disorder (present at birth), characterized by the reduction or absence of peroxisomes (cell structures that rid the body of toxic substances) in the cells of the liver, kidneys, and brain. ... In medicine (hematology), Gauchers disease (or Gaucher disease) is a genetic disorder that affects white blood cells, the spleen, bones and brain. ...

Manifestations and presentations

Because of the enormous number of these diseases and wide range of systems affected, nearly every "presenting complaint" to a doctor may have a congenital metabolic disease as a possible cause, especially in childhood. The following are examples of potential manifestations affecting each of the major organ systems:

• Growth failure, failure to thrive, weight loss
• Ambiguous genitalia, delayed puberty, precocious puberty
• Developmental delay, seizures, dementia, encephalopathy, stroke
• Deafness, blindness, pain agnosia
• Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps
• Dental abnormalities
• Immunodeficiency, thrombocytopenia, anemia, enlarged spleen, enlarged lymph nodes
• Many forms of cancer
• Recurrent vomiting, diarrhea, abdominal pain
• Excessive urination, renal failure, dehydration, edema
• Hypotension, heart failure, enlarged heart, hypertension, myocardial infarction
• Hepatomegaly, jaundice, liver failure
• Unusual facial features, congenital malformations
• Excessive breathing (hyperventilation, respiratory failure
• Abnormal behavior, depression, psychosis
• Joint pain, muscle weakness, cramps
• Hypothyroidism, adrenal insufficiency, hypogonadism, diabetes mellitus

Growth failure is a medical term for a pattern of a childs growth which is poorer than normal for age, sex, stage of maturation, and genetic height expectation. ... Failure to thrive - Wikipedia /**/ @import /skins/monobook/IE50Fixes. ... An intersexual is a person (or individual of any unisexual species) who is born with genitalia and/or secondary sexual characteristics of indeterminate sex, or which combine features of both sexes. ... Puberty is described as delayed when a boy or girl has passed the usual age of onset of puberty with no physical or hormonal signs that it is beginning. ... Precocious puberty means early puberty. ... Mental retardation (abbreviated as MR), is a term for a pattern of persistently slow learning of basic motor and language skills (milestones) during childhood, and a significantly below-normal intellectual capacity as an adult. ... This article is about the medical condition. ... Dementia (from Latin demens) is progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal aging. ... Encephalopathy is a container term for various conditions affecting the brain. ... A stroke or cerebrovascular accident (CVA) occurs when the blood supply to a part of the brain is suddenly interrupted by occlusion (an ischemic stroke- approximately 90%of strokes) or by hemorrhage (a hemorrhagic stroke - approximately 10% of strokes). ... This article is about hearing impairment in the patholocial sense. ... Blindness can be defined physiologically as the condition of lacking sight. ... For the manga by Tsukasa Hôjô, see Rash. ... In biology, pigment is any material resulting in color in plant or animal cells which is the result of selective absorption. ... Hypertrichosis is a medical term referring to a condition of excessive body hair. ... In medicine, immune deficiency (or immunodeficiency) is a state where the immune system is incapable of defending the organism from infectious disease. ... Thrombocytopenia (or -paenia, or thrombopenia in short) is the presence of relatively few platelets in blood. ... Anemia (American English) or anaemia (Commonwealth English), which literally means without blood, is a lack of red blood cells and/or hemoglobin. ... The spleen is a ductless, vertebrate gland that is not necessary for life but is closely associated with the circulatory system, where it functions in the destruction of old red blood cells and removal of other debris from the bloodstream, and also in holding a reservoir of blood. ... Structure of the lymph node. ... When normal cells are damaged or old they undergo apoptosis; cancer cells, however, avoid apoptosis. ... Vomiting (or emesis) is the forceful expulsion of the contents of ones stomach through the mouth. ... Diarrhea in American English, (spelled diarrhoea elsewhere) is a condition in which the sufferer has frequent and watery bowel movements (from the ancient Greek word διαρροή = leakage; lit. ... Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. ... Urination, also called micturition, is the process of disposing urine from the urinary bladder through the urethra to the outside of the body. ... Renal failure is when the kidneys fail to function properly. ... Dehydration is the removal of water (hydor in ancient Greek) from an object. ... Edema ( BE: oedema, formerly known as dropsy) is swelling of any organ or tissue due to accumulation of excess fluid. ... In physiology and medicine, hypotension refers to an abnormally low blood pressure. ... In medicine, hypertension refers to the problem of abnormally high blood pressure. ... A myocardial infarction occurs when an atherosclerotic plaque slowly builds up in the inner lining of a coronary artery and then suddenly ruptures, totally occluding the artery and preventing blood flow downstream. ... Hepatomegaly is an enlargement of the liver (swelling). ... Jaundice, technically known as icterus, is yellowing of the skin, sclera (eyes) and mucous membranes caused by increased levels of bilirubin in the system. ... Liver failure is the final stage of liver disease. ... A congenital disorder is a medical condition that is present at birth. ... In medicine, hyperventilation is the state of breathing faster or deeper than necessary, and thereby reducing the carbon dioxide concentration of the blood below normal. ... Respiratory failure is a medical term for inadequate gas exchange by the respiratory system. ... The word depression can mean: A decrease of functional activity in behavior patterns. ... Psychosis is a psychiatric classification for a mental state in which the perception of reality is distorted. ... A top-down view of skeletal muscle Muscle is a contractile form of tissue. ... Hypothyroidism is the disease state caused by insufficient thyroid hormone by the thyroid gland. ... In medicine, adrenal insufficiency is the inability of the adrenal gland to produce adequate amounts of cortisol in response to stress. ... Hypogonadism is a medical term for a defect of the reproductive system which results in lack of function of the gonads (ovaries or testes). ... Diabetes mellitus is a medical disorder characterized by varying or persistent hyperglycemia (elevated blood sugar levels), especially after eating. ...

Diagnostic techniques

Because of the multiplicity of conditions, many different diagnostic tests are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.

Common screening tests used in the last sixty years:

• Ferric chloride test (turned colors in reaction to various abnormal metabolites in urine)
• Ninhydrin paper chromatography (detected abnormal amino acid patterns)
• Guthrie bacterial inhibition assay (detected a few amino acids in excessive amounts in blood)
• Quantitative plasma amino acids, quantitative urine amino acids
• Urine organic acids by mass spectrometry

Specific diagnostic tests (or focused screening for a small set of disorders): Ninhydrin is a chemical that is used in criminal investigations that can detect latent fingerprints especially on porous surfaces. ... Paper chromatography is an analytical technique for separating and identifying pigments and other molecule from extracts that contain a complex mixture of molecules. ... In chemistry, an amino acid is any molecule that contains both amino and carboxylic acid functional groups. ... Mass spectrometry is a technique for separating ions by their mass-to-charge (m/z) ratios. ...

• Tissue biopsy or necropsy: liver, muscle, brain, bone marrow
• Skin biopsy and fibroblast cultivation for specific enzyme testing
• Specific DNA testing

A biopsy (in Greek: bios = life and opsy = look/appearance) is a medical test involving the removal of cells or tissues for examination. ... For the former Death Metal band called Autopsy, see Autopsy (band). ... The liver is an organ in vertebrates including humans. ... A top-down view of skeletal muscle Muscle is a contractile form of tissue. ... In the anatomy of animals, the brain, or encephalon, is the supervisory center of the nervous system. ... Bone marrow is the tissue comprising the center of large bones. ... Genetic fingerprinting or DNA testing is a technique to distinguish between individuals of the same species using only samples of their DNA. Its invention by Sir Alec Jeffreys at the University of Leicester was announced in 1985. ...

Newborn screening

Dozens of congenital metabolic diseases are now detectable by newborn screening tests, especially the expanded testing using mass spectrometry. This is an increasingly common way for the diagnosis to be made and sometimes results in earlier treatment and a better outcome. Newborn screening is the process of testing newborn babies for treatable genetic, endocrinologic, metabolic and hematologic abnormalities. ...

Management

In the middle of the 20th century the principal treatment for some of the amino acid disorders was restriction of dietary protein and all other care was simply management of complications. In the last two decades, enzyme replacement, gene transfer, and organ transplantation have become available and beneficial for many previously untreatable disorders. Some of the more common or promising are listed.

• Dietary restriction
  • E.g., reduction of dietary protein remains a mainstay of treatment for phenylketonuria and other amino acid disorders.
• Dietary supplementation or replacement
  • E.g., cornstarch several times a day helps prevent people with glycogen storage disease from becoming hypoglycemic as quickly.
• Vitamins
  • E.g., thiamine supplementation benefits several types of lactic acidosis.
• Intermediary metabolites, compounds, or drugs that facilitate or retard specific metabolic pathways
  • E.g.,
• Dialysis
  • E.g.,
• Enzyme replacement
  • E.g.,
• Gene transfer
  • E.g.,
• Bone marrow or organ transplantation
  • E.g.,
• Treatment of symptoms and complications
  • E.g.,
• Prenatal diagnosis and avoidance of pregnancy or abortion of an affected fetus
  • E.g.,

Phenylketonuria fee-nil-kee-ton-yur-ee-aah+ (PKU) is a human genetic disorder that occurs in about 1 in 15,000 births, but the incidence varies widely in different human populations from 1 in 4,500 births among the Irish to fewer than one in 100,000 births among... Glycogen storage disease is any one of several inborn errors of metabolism that result from enzyme defects that affect the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types. ... Hypoglycemia is a medical term referring to a pathologic state produced and usually defined by a lower than normal amount of sugar (glucose) in the blood. ... Thiamine mononitrate Thiamine or thiamin, also known as vitamin B1, is a colorless compound with chemical formula C12H17ClN4OS. It is soluble in water and insoluble in alcohol. ... Lactic acidosis is a condition caused by the buildup of lactic acid in the body. ...

References

More than most fields in medicine, this specialty has a single definitive, monumental text: The Metabolic and Molecular Bases of Inherited Disease, by Charles R. Scriver (Editor), William S. Sly (Editor), Barton Childs, Arthur L. Beaudet, David Valle, Kenneth W. Kinzler, Bert Vogelstein. New York:McGraw-Hill. 8th edition, 2001, 4 volumes, ISBN 0079130356

The most useful reference source on the web for these diseases is the Online Mendelian Inheritance database (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM) maintained by the National Library of Medicine.